Alternative Translational Products and Cryptic T Cell Epitopes: Expecting the Unexpected

Abstract

Although CD8 T cell epitopes have been studied extensively, often overlooked are unconventional cryptic epitopes generated from nontraditional sources of peptides/proteins and/or mechanisms of translation. In this review, we discuss alternative reading frame epitopes, both mechanistically and also in terms of their physiologic importance in the induction of antiviral and antitumor CTL responses. Issues of the influence of cryptic translational products on foreign and self-Ag diversity, thymic selection, and the T cell repertoire; disease pathogenesis; and approaches to vaccine design are discussed in context of the potentially large impact of unconventional epitopes on T cell immunity.

Predicting T cell recognition of MHC class I restricted neoepitopes

“…More recently, additional classes of unconventional epitopes have emerged and are being appreciated as valuable targets for cancer immunotherapy. 56–58 As more datasets about immunogenicity of such epitopes becomes available, our analysis should be expanded to cover them as well.…”

An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein

“…PRNP and ATXN1 are particular in that the overlapping ORFs are entirely comprised in the CDS of the reference proteins PrP and ATXN1, respectively. Overlapping ORFs are also involved in the generation of cryptic epitopes translated from self-proteins (45)(46)(47). It is tempting to speculate that alternative translation in eukaryotes has been overlooked and may significantly contribute to the proteome.…”

Alternative translation start sites and hidden coding potential of eukaryotic mRNAs

“…(63) It seems likely that the expression of small proteins and peptides encoded by either uORF or dORF, and unrelated to main protein product, is quite possible and these alternative cistrons have to be taken into account. (64) Sequence organization of eukaryotic mRNAs: evaluation of the frequency of alternative translation events and their contribution to proteome Despite the available experimental evidence of alternative translation events, the vast majority of eukaryotic mRNAs annotated in nucleotide sequence databanks was predicted to contain a single TIS and encode a single protein. It should be however noted that databanks contain predicted structures based on the available techniques of ORF mapping.…”